INDICATIONS & USAGE SECTION

Highlight: Dexlansoprazole is a proton pump inhibitor (PPI) indicated in patients 12 years of age and older for:

• Healing of all grades of erosive esophagitis (EE). (1.1)
• Maintenance of healed EE and relief of heartburn. (1.2)
• Treatment of symptomatic non-erosive gastroesophageal reflux disease (GERD). (1.3)

1 INDICATIONS AND USAGE

1.1 Healing of Erosive Esophagitis

Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for healing of all grades of erosive esophagitis (EE) for up to eight weeks.

1.2 Maintenance of Healed Erosive Esophagitis and Relief of Heartburn

Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older to maintain healing of EE and relief of heartburn for up to six months in adults and 16 weeks in patients 12 to 17 years of age.

1.3 Treatment of Symptomatic Non-Erosive Gastroesophageal Reflux Disease

Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for the treatment of heartburn associated with symptomatic non- erosive gastroesophageal reflux disease (GERD) for four weeks.

DOSAGE & ADMINISTRATION SECTION

Highlight: Recommended dosage in patients 12 years of age and older:

• See full prescribing information for complete dosing information for dexlansoprazole delayed-release capsules by indication and age group and dosage adjustment in patients with hepatic impairment. (2.1, 2.2)

Administration Instructions (2.3):

• Take without regard to food.
• Swallow whole; do not chew.
• See full prescribing information for alternative administration options.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage in Patients 12 Years of Age and Older

Table 1: Recommended Dexlansoprazole Delayed-Release Capsules****Dosage Regimen by Indication in Patients 12 Years of Age and Older********

2.2 Dosage Adjustment in Patients with Hepatic Impairment for the Healing

of Erosive Esophagitis

For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dosage is 30 mg dexlansoprazole delayed-release capsule once daily for up to eight weeks. Dexlansoprazole delayed-release capsule is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)].

2.3 Important Administration Information

• Take without regard to food.
• Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose.
• Swallow whole; do not chew.
• For patients who have trouble swallowing capsules, dexlansoprazole delayed-release capsules can be opened and administered with applesauce as follows:

1. Place one tablespoonful of applesauce into a clean container.
2. Open capsule.
3. Sprinkle intact granules on applesauce.
4. Swallow applesauce and granules immediately. Do not chew granules. Do not save the applesauce and granules for later use.

• Alternatively, the capsule can be administered with water via oral syringe or nasogastric (NG) tube.

Administration with Water in an Oral Syringe

1. Open the capsule and empty the granules into a clean container with 20 mL of water.
2. Withdraw the entire mixture into a syringe.
3. Gently swirl the syringe in order to keep granules from settling.
4. Administer the mixture immediately into the mouth. Do not save the water and granule mixture for later use.
5. Refill the syringe with 10 mL of water, swirl gently, and administer.
6. Refill the syringe again with 10 mL of water, swirl gently, and administer.

Administration with Water via a NG Tube (≥16 French)

1. Open the capsule and empty the granules into a clean container with 20 mL of water.
2. Withdraw the entire mixture into a catheter-tip syringe.
3. Swirl the catheter-tip syringe gently in order to keep the granules from settling, and immediately inject the mixture through the NG tube into the stomach. Do not save the water and granule mixture for later use.
4. Refill the catheter-tip syringe with 10 mL of water, swirl gently, and flush the tube.
5. Refill the catheter-tip syringe again with 10 mL of water, swirl gently, and administer.

---

WARNINGS AND PRECAUTIONS SECTION

Highlight: * Gastric Malignancy: In adults, symptomatic response with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. (5.1)

• Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients. (5.2)
• Clostridium difficile-Associated Diarrhea: PPI therapy may be associated with increased risk. (5.3)
• Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.4)
• Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. (5.5)
• Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue dexlansoprazole delayed-release capsules and refer to specialist for evaluation. (5.6)
• Cyanocobalamin (Vitamin B12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.7)
• Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs. (5.8)
• Interactions with Investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.9, 7)
• Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high-dose methotrexate administration, consider a temporary withdrawal of dexlansoprazole delayed-release capsules. (5.10, 7)
• Fundic Gland Polyps: Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. (5.11)
• Risk of Heart Valve Thickening in Pediatric Patients Less than Two Years of Age: Dexlansoprazole is not recommended in pediatric patients less than 2 years of age. (5.12, 8.4)

5 WARNINGS AND PRECAUTIONS

Dexlansoprazole Delayed-Release Capsules, 60 mg contain FD&C Yellow # 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow # 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non- specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue dexlansoprazole and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.3 Clostridium difficile-Associated Diarrhea

Published observational studies suggest that PPI therapy like dexlansoprazole may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

5.4 Bone Fracture

Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the conditions being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2), Adverse Reactions (6.2)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue dexlansoprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI-associated SLE is usually milder than nondrug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving dexlansoprazole delayed-release capsules, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Cyanocobalamin (Vitamin B12) Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with dexlansoprazole.

5.8 Hypomagnesemia and Mineral Metabolism

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].

Consider monitoring magnesium and calcium levels prior to initiation of dexlansoprazole delayed-release capsules and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.9 Interactions with Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop dexlansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7), Clinical Pharmacology (12.2)].

5.10 Interaction with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)].

5.11 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

5.12 Risk of Heart Valve Thickening in Pediatric Patients Less Than Two

Years of Age

Dexlansoprazole is not recommended in pediatric patients less than two years of age. Nonclinical studies in juvenile rats with lansoprazole have demonstrated an adverse effect of heart valve thickening. Dexlansoprazole is the R-enantiomer of lansoprazole [see Use in Specific Populations (8.4)].

---

USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: Based on animal data, may cause adverse effects on fetal bone growth and development. (8.1)

• Pediatrics: Based on data with lansoprazole, dexlansoprazole is not effective in patients with symptomatic GERD 1 month to less than 1 year of age and nonclinical studies have demonstrated adverse effects in juvenile rats. (8.4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no studies with dexlansoprazole use in pregnant women to inform a drug-associated risk. Dexlansoprazole is the R-enantiomer of lansoprazole, and published observational studies of lansoprazole use during pregnancy did not demonstrate an association of adverse pregnancy-related outcomes with lansoprazole (see Data).

In animal reproduction studies, oral administration of lansoprazole to rats during organogenesis through lactation at 1.8 times the maximum recommended human dexlansoprazole dose produced reductions in the offspring in femur weight, femur length, crown-rump length and growth plate thickness (males only) on postnatal Day 21 (see Data). These effects were associated with reduction in body weight gain. Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Dexlansoprazole is the R-enantiomer of lansoprazole. Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs. There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, [95% Confidence Interval (CI) 0.25 to 4.21]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. A meta- analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, [95% CI 0.86 to 1.45] and for spontaneous abortions OR=1.29, [95% CI 0.84 to 1.97]).

Animal Data

An embryo-fetal development study conducted in rabbits at oral dexlansoprazole doses up to 30 mg/kg/day (approximately nine times the maximum recommended human dexlansoprazole dose [60 mg/day] based on body surface area) during organogenesis showed no effects on fetuses due to dexlansoprazole. In addition, embryo-fetal development studies performed in rats with oral lansoprazole at doses up to 150 mg/kg/day (40 times the recommended human lansoprazole dose based on body surface area) during organogenesis and in rabbits with oral lansoprazole at doses up to 30 mg/kg/day (16 times the recommended human lansoprazole dose based on body surface area) during organogenesis revealed no effects on fetuses due to lansoprazole.

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of 10 to 100 mg/kg/day (0.2 to 1.8 times the maximum recommended human dexlansoprazole dose of 60 mg based on dexlansoprazole AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation. Maternal effects observed at 100 mg/kg/day (1.8 times the maximum recommended human dexlansoprazole dose of 60 mg based on dexlansoprazole AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption. The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity. Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks. The effects on bone parameters were associated with reduction in body weight gain.

8.2 Lactation

Risk Summary

There is no information regarding the presence of dexlansoprazole in human milk, the effects on the breastfed infant, or the effects on milk production. However, lansoprazole and its metabolites are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dexlansoprazole and any potential adverse effects on the breastfed child from dexlansoprazole or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of dexlansoprazole have been established in pediatric patients 12 years to 17 years of age for the healing of all grades of EE, the maintenance of healed EE and relief of heartburn, and treatment of heartburn associated with symptomatic non-erosive GERD. Use of dexlansoprazole in this age group is supported by evidence from adequate and well-controlled studies of dexlansoprazole in adults with additional safety, efficacy and pharmacokinetic data in pediatric patients 12 to 17 years of age. The adverse reaction profile in patients 12 to 17 years of age was similar to adults [see Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)].

The safety and effectiveness of dexlansoprazole have not been established in pediatric patients less than 12 years of age.

Dexlansoprazole is not recommended in pediatric patients less than two years of age [see Warnings and Precautions (5.12)]. Nonclinical studies in juvenile rats treated with lansoprazole (the racemic mixture) have demonstrated adverse effects of heart valve thickening and bone changes at dexlansoprazole exposures which are expected to be similar to or higher than the dexlansoprazole exposure in pediatric patients one year to two years of age, as described below in Juvenile Animal Toxicity Data.

The use of dexlansoprazole is not recommended for the treatment of symptomatic GERD in pediatric patients one month to less than one year of age because lansoprazole was not shown to be effective in a multicenter, double-blind controlled trial.

Juvenile Animal Toxicity Data

Heart Valve Thickening

In two oral toxicity studies, thickening of the mitral heart valve occurred in juvenile rats treated with lansoprazole. Heart valve thickening was observed primarily with oral dosing initiated on postnatal Day 7 (age equivalent to neonatal humans) and postnatal Day 14 (human age equivalent of approximately one year) at doses of 250 mg/kg/day and higher (at postnatal Day 7 and postnatal Day 14 respectively, 2.5 and 1.8 times the expected dexlansoprazole exposure based on AUC in pediatric patients one year to two years of age). The treatment durations associated with heart valve thickening ranged from 5 days to 8 weeks. The findings reversed or trended towards reversibility after a 4-week drug-free recovery period. The incidence of heart valve thickening after initiation of dosing on postnatal Day 21 (human age equivalent of approximately two years) was limited to a single rat (1/24) in groups given 500 mg/kg/day for 4 or 8 weeks (2.1 times the expected dexlansoprazole exposure based on AUC in pediatric patients one year to two years of age). Based on the low incidence of heart valve thickening in 21-day old rats and the equivalent human age, the risk of heart valve injury does not appear to be relevant to patients two years of age and older.

Bone Changes

In an eight-week oral toxicity study of lansoprazole in juvenile rats with dosing initiated on postnatal Day 7, doses equal to or greater than 100 mg/kg/day (dexlansoprazole exposure based on AUC approximately equal to that in pediatric patients one year to two years of age) produced delayed growth, with impairment of weight gain observed as early as postnatal Day 10 (age equivalent to neonatal humans). At the end of treatment, the signs of impaired growth at 100 mg/kg/day and higher included reductions in body weight (14 to 44% compared to controls), absolute weight of multiple organs, femur weight, femur length and crown-rump length. Femoral growth plate thickness was reduced only in males and only at the 500 mg/kg/day dose. The effects related to delayed growth persisted through the end of the four-week recovery period. Longer term data were not collected.

8.5 Geriatric Use

Of the total number of patients (n=4,548) in clinical studies of dexlansoprazole, 11% of patients were aged 65 years and over, while 2% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No dosage adjustment for dexlansoprazole delayed-release capsules is necessary for patients with mild hepatic impairment (Child-Pugh Class A).

In a study of adult patients with moderate hepatic impairment (Child-Pugh Class B) who received a single dose of 60 mg dexlansoprazole, there was a significant increase in systemic exposure of dexlansoprazole compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, for patients with moderate hepatic impairment (Child-Pugh Class B), dosage reduction is recommended for the healing of EE [see Dosage and Administration (2.2)].

No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); the use of dexlansoprazole delayed-release capsules is not recommended for these patients [see Dosage and Administration (2.2)].

---

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Healing of Erosive Esophagitis in Adults

Two multicenter, double-blind, active-controlled, randomized, eight week studies were conducted in patients with endoscopically confirmed EE. Severity of the disease was classified based on the Los Angeles Classification Grading System (Grades A to D). Patients were randomized to one of the following three treatment groups: Dexlansoprazole 60 mg once daily, dexlansoprazole 90 mg once daily or lansoprazole 30 mg once daily. Patients who were H. pylori positive or who had Barrett’s Esophagus and/or definite dysplastic changes at baseline were excluded from these studies. A total of 4,092 patients were enrolled and ranged in age from 18 to 90 years (median age 48 years) with 54% male. Race was distributed as follows: 87% Caucasian, 5% Black and 8% Other. Based on the Los Angeles Classification, 71% of patients had mild EE (Grades A and B) and 29% of patients had moderate to severe EE (Grades C and D) before treatment.

The studies were designed to test noninferiority. If noninferiority was demonstrated then superiority would be tested. Although noninferiority was demonstrated in both studies, the finding of superiority in one study was not replicated in the other.

The proportion of patients with healed EE at Week 4 or 8 is presented below in Table 8.

Table 8: EE Healing Rates in Adults: All Grades*

CI = Confidence interval

*Based on crude rate estimates, patients who did not have endoscopically documented healed EE and prematurely discontinued were considered not healed.

†Patients with at least one postbaseline endoscopy.

‡Primary efficacy endpoint.

§Demonstrated noninferiority to lansoprazole.

Dexlansoprazole 90 mg once daily was studied and did not provide additional clinical benefit over dexlansoprazole 60 mg once daily.

14.2 Maintenance of Healed Erosive Esophagitis and Relief of Heartburn in

Adults

A multicenter, double-blind, placebo-controlled, randomized study was conducted in patients who successfully completed an EE study and showed endoscopically confirmed healed EE. Maintenance of healing and symptom resolution over a six month period was evaluated with dexlansoprazole 30 mg or 60 mg capsules once daily compared to placebo. A total of 445 patients were enrolled and ranged in age from 18 to 85 years (median age 49 years), with 52% female. Race was distributed as follows: 90% Caucasian, 5% Black and 5% Other.

Sixty-six percent of patients treated with 30 mg of dexlansoprazole capsules remained healed over the six month time period as confirmed by endoscopy (see Table 9).

Table 9: Maintenance Rates of Healed EE at Month 6 in Adults*

*Based on crude rate estimates, patients who did not have endoscopically documented relapse and prematurely discontinued were considered to have relapsed.

†Patients with at least one postbaseline endoscopy

‡Statistically significant vs placebo

Dexlansoprazole 60 mg capsules once daily was studied and did not provide additional clinical benefit over dexlansoprazole 30 mg capsules once daily.

The effect of dexlansoprazole 30 mg capsules on maintenance of relief of heartburn was also evaluated. Upon entry into the maintenance study, a majority of patients’ baseline heartburn severity was rated as none. Dexlansoprazole 30 mg capsules demonstrated a statistically significantly higher percent of 24 hour heartburn-free periods compared to placebo over the six month treatment period (see Table 10). The majority of patients treated with placebo discontinued due to relapse of EE between Month 2 and Month 6.

Table 10: Median Percentage of 24 Hour Heartburn-Free Periods of the Maintenance of Healed EE Study in Adults

*Secondary efficacy endpoint

†Statistically significant vs placebo

14.3 Treatment of Symptomatic Non-Erosive GERD in Adults

A multicenter, double-blind, placebo-controlled, randomized, four week study was conducted in patients with a diagnosis of symptomatic non-erosive GERD made primarily by presentation of symptoms. These patients who identified heartburn as their primary symptom, had a history of heartburn for six months or longer, had heartburn on at least four of seven days immediately prior to randomization and had no esophageal erosions as confirmed by endoscopy. However, patients with symptoms which were not acid-related may not have been excluded using these inclusion criteria. Patients were randomized to one of the following treatment groups: Dexlansoprazole 30 mg daily, 60 mg daily, or placebo. A total of 947 patients were enrolled and ranged in age from 18 to 86 years (median age 48 years) with 71% female. Race was distributed as follows: 82% Caucasian, 14% Black and 4% Other.

Dexlansoprazole 30 mg capsules provided statistically significantly greater percent of days with heartburn-free 24 hour periods over placebo as assessed by daily diary over four weeks (see Table 11). Dexlansoprazole 60 mg capsules once daily was studied and provided no additional clinical benefit over dexlansoprazole 30 mg capsules once daily.

Table 11: Median Percentages of 24 Hour Heartburn-Free Periods During the 4 Week Treatment Period of the Symptomatic Non-Erosive GERD Study in Adults

*Statistically significant vs placebo

A higher percentage of patients on dexlansoprazole 30 mg capsules had heartburn-free 24 hour periods compared to placebo as early as the first three days of treatment and this was sustained throughout the treatment period (percentage of patients on Day 3: dexlansoprazole 38% versus placebo 15%; on Day 28: dexlansoprazole 63% versus placebo 40%).

14.4 Pediatric GERD

Use of dexlansoprazole in patients 12 to 17 years of age is supported by evidence from adequate and well-controlled studies of dexlansoprazole capsules in adults, with additional safety, efficacy, and pharmacokinetic data from studies performed in pediatric patients.

Healing of EE, Maintenance of Healed EE and Relief of Heartburn

In a multicenter, 36 week trial, 62 patients 12 to 17 years of age with a documented history of GERD for at least three months and endoscopically-proven erosive esophagitis (EE) were enrolled to evaluate the healing of EE, maintenance of healed EE and relief of heartburn, followed by an additional 12 weeks without treatment.

The median age was 15 years, with males accounting for 61% of the patients. Based on the Los Angeles Classification Grading Scale, 97% of patients had mild EE (Grades A and B), and 3% of patients had moderate to severe EE (Grades C and D) before treatment.

In the first eight weeks, 62 patients were treated with dexlansoprazole 60 mg capsules once daily to evaluate the healing of EE. Of the 62 patients, 58 patients completed the eight week trial, and 51 (88%) patients achieved healing of EE, as confirmed by endoscopy, over eight weeks of treatment (see Table 12).

Table 12. Healing of EE at Week 8 in Pediatric Patients 12 to 17 Years of Age

• Includes only patients who underwent postbaseline endoscopy.

† Reported are the exact confidence limits.

After the initial eight weeks of treatment, all 51 patients with healed EE were randomized to receive treatment with dexlansoprazole 30 mg capsules or placebo, once daily for an additional 16 weeks to evaluate maintenance of healing and symptom resolution. Maintenance of healing was assessed by endoscopy at Week 24. Of the 51 patients randomized, 13 patients discontinued early. Of these, five patients did not undergo postbaseline endoscopy. Eighteen of 22 (82%) evaluable patients treated with dexlansoprazole 30 mg capsules remained healed over the 16 week treatment period as confirmed by endoscopy, compared with 14 of 24 (58%) in placebo (see Table 13).

Table 13. Maintenance of Healed EE at Week 24 in Pediatric Patients 12 to 17 Years of Age*

• Following eight weeks of initial therapy and 16 weeks of maintenance therapy.

† Includes patients with at least one postbaseline endoscopy.

‡ Reported are the exact confidence limits.

Relief of heartburn was assessed in randomized patients during the 16 week maintenance period. The median percentage of 24 hour heartburn-free periods was 87% for those receiving dexlansoprazole 30 mg capsules compared to 68% for those receiving placebo.

Out of the 32 patients who maintained healing of EE at the end of the 16 week maintenance period, 27 patients (16 treated with dexlansoprazole and 11 treated with placebo during the double-blind phase) were followed for an additional 12 weeks without therapy. Twenty-four of the 27 patients completed the 12 week follow-up period. One patient required treatment with acid suppression therapy.

Treatment of Symptomatic Non-Erosive GERD

In a single-arm, open-label, multicenter trial, 104 pediatric patients 12 to 17 years of age with symptomatic non-erosive GERD were treated with dexlansoprazole 30 mg capsules once daily, for four weeks to evaluate safety and effectiveness. Patients had a documented history of GERD symptoms for at least three months prior to screening, reported heartburn on at least three out of seven days during screening, and had no esophageal erosions as confirmed by endoscopy. The median age was 15 years, with females accounting for 70% of the patients. During the four week treatment period, the median percentage of 24 hour heartburn free periods was 47%.

---

NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two, 24 month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg/kg/day, about one to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg/day.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology (12.2)].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day (four to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24 month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg/kg/day, two to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole/kg/day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole/kg/day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the recommended human lansoprazole dose based on BSA).

A 26 week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test.

Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

---

SPL MEDGUIDE SECTION

MEDICATION GUIDE

---

INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE

---